Is ABCB5 p.Phe784Cys (c.2351T>G) pathogenic?

ABCB5 p.Phe784Cys (c.2351T>G) is classified Uncertain significance in ABCB5 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.7156); Rare (popmax 0.853%, afr).

How common is ABCB5 p.Phe784Cys (c.2351T>G) in the general population?

ABCB5 p.Phe784Cys (c.2351T>G) is rare (popmax 0.853%, afr) (gnomAD).

What do computational predictors say about ABCB5 p.Phe784Cys (c.2351T>G)?

AlphaMissense predicts likely pathogenic (score 0.7156) — an in-silico prediction, not a clinical call.

ABCB5 p.Phe784Cys

c.2351T>G · VCV4105647

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7156 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.853%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7156	likely pathogenic
REVEL	0.817	moderately pathogenic-leaning
SaProt	LLR -13.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.20	unconstrained · MANE · 132 kb · p 2.2e-15 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.853% African / African-American · 640/75,004 alleles

Filtering AF 0.799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.777%

Overall 0.0491% 792/1,613,544 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.853%	117
Remaining individualsnot grpmax-eligible	0.0688%	1,453
Admixed American	0.0467%	2,143
European (non-Finnish)	0.00644%	15,523
South Asian	0.00549%	18,203

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: ABCB5
Protein: p.Phe784Cys
Coding: c.2351T>G
MANE Select: NM_001163941
Type: single nucleotide variant
Location: chr7:20704737 (GRCh38)
Gene constraint: LOEUF 1.178 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.01
Residue 784: the abc transmembrane type-1 2 domain

Full ABCB5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ABCB5 p.Ala350Thr Likely benign ★★ ⚠ same type
ABCB5 p.Val1209Ala Likely benign ★★ ⚠ same type
ABCB5 p.Ala1112Thr Uncertain significance ★ ⚠ same type
ABCB5 p.Ala1154Gly Uncertain significance ★ ⚠ same type
ABCB5 p.Ala221Val Uncertain significance ★ ⚠ same type
ABCB5 p.Ala223Ser Uncertain significance ★ ⚠ same type
ABCB5 p.Ala327Thr Uncertain significance ★ ⚠ same type
ABCB5 p.Ala501Glu Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/abcb5-p-phe784cys (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown